U.S. patent application number 10/348716 was filed with the patent office on 2003-07-24 for use of organic compounds.
Invention is credited to Resta, Debra Jane, Sizer, Kurt Clement, Traxler, Peter.
Application Number | 20030139430 10/348716 |
Document ID | / |
Family ID | 26995853 |
Filed Date | 2003-07-24 |
United States Patent
Application |
20030139430 |
Kind Code |
A1 |
Resta, Debra Jane ; et
al. |
July 24, 2003 |
Use of organic compounds
Abstract
This disclosure relates to the treatment of cancer, particularly
breast cancer, with a combination an aromatase inhibitor, such as
letrozole, and a compound that inhibits the tyrosine kinase
activity of epidermal growth factor (EGF). Methods of treatment and
pharmaceutical compositions are included in the disclosure.
Inventors: |
Resta, Debra Jane;
(Somerset, NJ) ; Sizer, Kurt Clement; (Hoboken,
NJ) ; Traxler, Peter; (Schonenbuch, CH) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS, CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 430/2
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
26995853 |
Appl. No.: |
10/348716 |
Filed: |
January 22, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60351591 |
Jan 24, 2002 |
|
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Current U.S.
Class: |
514/265.1 |
Current CPC
Class: |
A61K 31/519 20130101;
A61K 31/519 20130101; A61K 31/4196 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/4196 20130101 |
Class at
Publication: |
514/265.1 |
International
Class: |
A61K 031/519 |
Claims
What is claimed is:
1. A combination which comprises (a) letrozole and (b) a
7H-pyrrolo[2,3-d]pyrimidine derivative of formula I 2wherein q is
1, R.sub.2 is phenyl substituted by hydroxy, and R.sub.6 is
hydrogen or methyl; in which the active ingredients (a) and (b) are
present in each case in free form or in the form of a
pharmaceutically acceptable salt and optionally at least one
pharmaceutically acceptable carrier; for simultaneous, separate or
sequential use.
2. Combination according to claim 1 comprising a
7H-pyrrolo[2,3-d]pyrimidi- ne derivative of formula I wherein q is
1, R.sub.2 is phenyl substituted by 4-hydroxy, and R.sub.6 is
methyl.
3. Combination according to claim 1 or 2 which is a combined
preparation or a pharmaceutical composition.
4. Method of treating a warm-blooded animal having a solid tumor
disease which comprises administering to the animal a combination
according to any one of claims 1 to 3 in a quantity which is
jointly therapeutically effective against said tumor disease and in
which the compounds can also be present in the form of their
pharmaceutically acceptable salts.
5. Method of inhibiting the formation of metastases in a
warm-blooded animal having a breast tumor disease which comprises
administering to the patient a pharmaceutically effective amount of
a combination according to any one of claims 1 to 3 in a quantity
which is jointly therapeutically effective against said tumor
disease and in which the compounds can also be present in the form
of their pharmaceutically acceptable salts.
6. Method according to claim 4 or 5 which comprises administering
the 7H-pyrrolo[2,3-d]pyrimidine derivative of formula I, or a salt
thereof, to the human subject over at least a three week time
period on only about 40% to about 71% of the days in the time
period.
7. Method of claim 4 or 5 wherein the pharmaceutically effective
daily dose of the 7H-pyrrolo[2,3-d]pyrimidine derivative of formula
1, or a salt thereof, is in the range from about 50 mg to about
2000 mg.
8. A pharmaceutical composition comprising a quantity which is
jointly therapeutically effective against a solid tumor disease of
a pharmaceutical combination according to any one of claims 1 to 3
and at least one pharmaceutically acceptable carrier.
9. Use of letrozole in combination with a
7H-pyrrolo[2,3-d]pyrimidine derivative of formula I 3wherein q is
1, R.sub.2 is phenyl substituted by hydroxy, and R.sub.6 is
hydrogen or methyl, for the preparation of a medicament for the
treatment of a solid tumor disease.
10. A commercial package comprising (a) letrozole and (b) a
7H-pyrrolo[2,3-d]pyrimidine derivative of formula I 4wherein q is
1, R.sub.2 is phenyl substituted by hydroxy, and R.sub.6 is
hydrogen or methyl; together with instructions for simultaneous,
separate or sequential use thereof in the treatment of a solid
tumor disease.
Description
[0001] The invention relates to a pharmaceutical combination which
comprises (a) letrozole and (b) a 7H-pyrrolo[2,3-d]pyrimidine
derivative of formula I (see below) and optionally at least one
pharmaceutically acceptable carrier for simultaneous, separate or
sequential use, in particular for the treatment of a solid tumor
disease; a pharmaceutical composition comprising such a
combination; the use of such a combination for the preparation of a
medicament for the treatment of a solid tumor disease; a commercial
package or product comprising such a combination as a combined
preparation for simultaneous, separate or sequential use; and to a
method of treatment of a warm-blooded animal, especially a
human.
[0002] Letrozole inhibits in humans the estrogen production, i.e.
the conversion of the substrates androstenedione and testosterone
to estrone and estradiol, respectively. The compound is
particularly useful for the treatment of hormone receptor positive
breast tumors.
[0003] Compounds which inhibit the tyrosine kinase activity of the
epidermal growth factor (EGF) receptor are useful, for example, in
the treatment of benign or malignant tumours. They are capable of
preventing the formation of tumour metastases and the growth of
micro-metastases. They can be used especially in the case of
epidermal hyperproliferation (psoriasis), in the treatment of
neoplasias of epithelial character and in leukemias. The
7H-pyrrolo[2,3-d]pyrimidines disclosed in WO 97/02266 represent
inhibitors of the EGF receptor tyrosine kinase activity.
[0004] Surprisingly, it has now been found that the
anti-proliferative effect of a combination which comprises
letrozole and 7H-pyrrolo[2,3-d]pyrimidine derivatives of formula I
1
[0005] wherein q is 1, R.sub.2 is phenyl substituted by hydroxy,
and R.sub.6 is hydrogen or methyl; is greater than the maximum
effect that can be achieved with either type of ingredient
alone.
[0006] Hence, the present invention pertains to a combination, such
as a combined preparation or a pharmaceutical composition, which
comprises (a) letrozole and (b) a 7H-pyrrolo[2,3-d]pyrimidine
derivative of formula I as defined above in which the active
ingredients (a) and (b) are present in each case in free form or in
the form of a pharmaceutically acceptable salt and optionally at
least one pharmaceutically acceptable carrier; for simultaneous,
separate or sequential use, in particular for the treatment of a
solid tumor disease.
[0007] The term "a combined preparation", as used herein defines
especially a "kit of parts" in the sense that the combination
partners (a) and (b) as defined above can be dosed independently or
by use of different fixed combinations with distinguished amounts
of the combination partners (a) and (b), i.e., simultaneously or at
different time points. The parts of the kit of parts can then,
e.g., be administered simultaneously or chronologically staggered,
that is at different time points and with equal or different time
intervals for any part of the kit of parts. Very preferably, the
time intervals are chosen such that the effect on the treated
disease in the combined use of the parts is larger than the effect
which would be obtained by use of only any one of the combination
partners (a) and (b). The ratio of the total amounts of the
combination partner (a) to the combination partner (b) to be
administered in the combined preparation can be varied, e.g. in
order to cope with the needs of a patient sub-population to be
treated or the needs of the single patient which different needs
can be due to age, sex, body weight, etc. of the patients.
Preferably, there is at least one beneficial effect, e.g., a mutual
enhancing of the effect of the combination partners (a) and (b), in
particular a synergism, e.g. a more than additive effect,
additional advantageous effects, less side effects, a combined
therapeutical effect in a non-effective dosage of one or both of
the combination partners (a) and (b), and very preferably a strong
synergism of the combination partners (a) and (b).
[0008] The term "treatment" comprises the administration of the
combination partners to a warm-blooded animal in need of, such
treatment with the aim to effect a delay of progression of a
disease. The term delay of "progression" as used herein means
administration of the combination to patients being in a pre-stage
or in an early phase of the proliferative disease to be treated, in
which patients for example a pre-form of the corresponding disease
is diagnosed or which patients are in a condition, e.g. during a
medical treatment or a condition resulting from an accident, under
which it is likely that a corresponding disease will develop.
[0009] The term "a solid tumor disease" especially means breast
cancer, ovarian cancer, cancer of the colon and generally the GI
tract, cervix cancer, lung cancer, e.g. small-cell lung cancer and
non-small-cell lung cancer, head and neck cancer, renal cancer,
bladder cancer, cancer of the prostate, glioma or Kaposi's
sarcoma.
[0010] Letrozole can be prepared as described in U.S. Pat. No.
5,473,078. It can be administered, e.g., as described in U.S. Pat.
No. 4,978,672 or U.S. Pat. No. 5,473,078, or in the form as it is
marketed, e.g. under the trademark FEMARA.TM. or FEMAR.TM..
[0011] The 7H-pyrrolo[2,3-d]pyrimidines of formula I can be
prepared and administered as disclosed in WO 97/02266. Preferably,
the compounds of formula I are administered orally, e.g., in hard
gelatin capsules.
[0012] The compounds used as combination partners (a) and (b)
disclosed herein can be prepared and administered as described in
the cited documents, respectively. The combination partners (a) or
(b) and their salts may also be used in the form of a hydrate or
include other solvents used for crystallization.
[0013] A combination which comprises (a) letrozole and (b) a
compound of formula I wherein q is 1, R.sub.2 is phenyl substituted
by hydroxy, and R.sub.6 is hydrogen or methyl, in which the active
ingredients are present in each case in free form or in the form of
a pharmaceutically acceptable salt and optionally at least one
pharmaceutically acceptable carrier, will be referred to
hereinafter as a COMBINATION OF THE INVENTION.
[0014] The COMBINATIONS OF THE INVENTION inhibits the growth of
solid tumors. In one preferred embodiment of the invention, the
solid tumor disease to be treated with a COMBINATION OF THE
INVENTION is breast cancer, in particular advanced breast cancer in
post-menopausal women, and especially breast cancer wherein the
tumors are either estrogen-receptor and/or progesterone-receptor
positive and/or positive for type 1 growth factors (EGFR/HER2).
Furthermore, the COMBINATIONS OF THE INVENTION is in particular
suitable for the treatment of breast cancer which is at least
partially resistant to the treatment with tamoxifen.
[0015] The nature of solid tumor diseases is multifactorial. Under
certain circumstances, drugs with different mechanisms of action
may be combined. However, just considering any combination of drugs
having different mode of action does not necessarily lead to
combinations with advantageous effects.
[0016] All the more surprising is the experimental finding that in
vivo the administration of a COMBINATION OF THE INVENTION compared
to a monotherapy applying only one of the pharmaceutically active
ingredients used in the COMBINATION OF THE INVENTION results not
only in a more beneficial, especially synergistic, e.g.
anti-proliferative effect, e.g. with regard to the delay of
progression of a proliferative disease or with regard to a change
in tumor volume, but also in further surprising beneficial effects,
e.g. less side-effects and a decreased mortality and morbidity.
Furthermore, depending on the particular tumor type a decrease of
the tumor volume can be obtained when using a COMBINATION OF THE
INVENTION in cases in which by monotherapy no decrease of the tumor
volume can be achieved. The COMBINATIONS OF THE INVENTION are also
suitable to prevent the metastatic spread of tumors and the growth
or development of micrometastases. The COMBINATIONS OF THE
INVENTION are in particular suitable for the treatment of patients
with advanced cancer who have failed standard systemic therapy.
This includes patients having tumor types showing resistance to
monotherapy, especially monotherapy with tamoxifen, or showing
resistance to combinations different from those disclosed
herein.
[0017] A further benefit is that lower doses of the active
ingredients of the COMBINATION OF THE INVENTION can be used, for
example, that the dosages need not only often be smaller, but are
also applied less frequently, or can be used in order to diminish
the incidence of side-effects observed with one of the combination
partners alone. This is in accordance with the desires and
requirements of the patients to be treated.
[0018] It can be shown by established test models that a
COMBINATION OF THE INVENTION results in the beneficial effects
described herein-before. The person skilled in the pertinent art is
fully enabled to select a relevant test model to prove such
beneficial effects. The pharmacological activity of a COMBINATION
OF THE INVENTION may, for example, be demonstrated in a clinical
study or in a test procedure as essentially described
hereinafter.
[0019] Suitable clinical studies are, e.g., randomized,
double-blind, placebo-controlled, parallel studies in female breast
cancer patients with advanced disease having tumors which are
either estrogen-receptor and/or progesterone-receptor positive.
Such studies are, in particular, suitable to compare the effects of
amonotherapy using the active ingredients and a therapy using a
COMBINATION OF THE INVENTION, and to prove in particular the
synergism of the active ingredients of the COMBINATIONS OF THE
INVENTION. The primary endpoints in such studies can be the effect
on pain scores, analgesic use, performance status, Quality of Life
scores, time to progression of the disease, morbidity or mortality.
The radiologic evaluation of tumors in regular time periods, e.g.
every 8 or 12 weeks, is a suitable approach to determine the effect
of the COMBINATION OF THE INVENTION. In a suitable study design,
patients are, for example, randomized in a double-blind fashion
receiving letrozole in a daily dose of 2.5 mg in addition to a
daily dose of 200, 400, 600 or 800 mg PKI166 or a corresponding
placebo. The minimum duration of such a study should be about 6 or
12 months.
[0020] It is one objective of this invention to provide a
pharmaceutical composition comprising a quantity, which is jointly
therapeutically effective against a proliferative disease
comprising the COMBINATION OF THE INVENTION. In this composition,
the combination partners (a) and (b) can be administered together,
one after the other or separately in one combined unit dosage form
or in two separate unit dosage forms. The unit dosage form may also
be a fixed combination.
[0021] The pharmaceutical compositions according to the invention
can be prepared in a manner known per se and are those suitable for
enteral, such as oral or rectal, and parenteral administration to
mammals (warm-blooded animals), including man, comprising a
thera-peutically effective amount of at least one pharmacologically
active combination partner alone or in combination with one or more
pharmaceutically acceptable carries, especially suitable for
enteral or parenteral application. In one embodiment of the
invention, one or more of the active ingredients are administered
intraveniously.
[0022] The novel pharmaceutical composition contain, for example,
from about 10% to about 100%, preferably from about 20% to about
60%, of the active ingredients. Pharmaceutical preparations for the
combination therapy for enteral or parenteral administration are,
for example, those in unit dosage forms, such as sugar-coated
tablets, tablets, capsules or suppositories, and furthermore
ampoules. If not indicated otherwise, these are prepared in a
manner known per se, for example by means of conventional mixing,
granulating, sugar-coating, dissolving or lyophilizing processes.
It will be appreciated that the unit content of a combination
partner contained in an individual dose of each dosage form need
not in itself constitute an effective amount since the necessary
effective amount can be reached by administration of a plurality of
dosage units.
[0023] In particular, a therapeutically effective amount of each of
the combination partners of the COMBINATION OF THE INVENTION may be
administered simultaneously or sequentially and in any order, and
the components may be administered separately or as a fixed
combination. For example, the method of treatment of a solid tumor
disease according to the invention may comprise (i) administration
of the first combination partner in free or pharmaceutically
acceptable salt form and (ii) adminstration of the second
combination partner in free or pharmaceutically acceptable salt
form, simultaneously or sequentially in any order, in jointly
therapeutically effective amounts, preferably in synergistically
effective amounts, e.g. in daily dosages corresponding to the
amounts described herein. The individual combination partners of
the COMBINATION OF THE INVENTION can be administered separately at
different times during the course of therapy or concurrently in
divided or single combination forms. Furthermore, the term
administering also encompasses the use of a pro-drug of a
combination partner that convert in vivo to the combination partner
as such. The instant invention is therefore to be understood as
embracing all such regimes of simultaneous or alternating treatment
and the term "administering" is to be interpreted accordingly.
[0024] The effective dosage of each of the combination partners
employed in the COMBINATION OF THE INVENTION may vary depending on
the particular compound or pharmaceutical composition employed, the
mode of administration, the condition being treated, the severity
of the condition being treated. Thus, the dosage regimen the
COMBINATION OF THE INVENTION is selected in accordance with a
variety of factors including the route of administration and the
renal and hepatic function of the patient. A physician, clinician
or veterinarian of ordinary skill can readily determine and
prescribe the effective amount of the single active ingredients
required to prevent, counter or arrest the progress of the
condition. Optimal precision in achieving concentration of the
active ingredients within the range that yields efficacy without
toxicity requires a regimen based on the kinetics of the active
ingredients' availability to target sites. This involves a
consideration of the distribution, equilibrium, and elimination of
the active ingredients.
[0025] When the combination partners employed in the COMBINATION OF
THE INVENTION are applied in the form as marketed as single drugs,
their dosage and mode of administration can take place in
accordance with the information provided on the package insert of
the respective marketed drug in order to result in the beneficial
effect described herein, if not mentioned herein otherwise.
[0026] In particular, if the the warm-blooded animal is a human,
the dosage of a compound of formula I is preferably in the range of
about is in the range from about 50 mg to about 2000 mg/day.
[0027] Letrozole is preferably administered daily according to the
package insert at a dose of 2.5 mg.
[0028] Preferably, a compound of formula I is employed wherein q is
1, n is 0, R.sub.1 is hydrogen, R.sub.2 is phenyl substituted by
4-hydroxy, and R.sub.6 is methyl. This particular compound is also
known as "PKI166".
[0029] The COMBINATION OF THE INVENTION can be a combined
preparation or a pharmaceutical composition.
[0030] Moreover, the present invention relates to a method of
treating a warm-blooded animal having a solid tumor disease
comprising administering to the animal a COMBINATION OF THE
INVENTION in a quantity which is jointly therapeutically effective
against a solid tumor disease and in which the combination partners
can also be present in the form of their pharmaceutically
acceptable salts. Furthermore, the treatment can comprise surgery,
radiotherapy, cryotherapy and immunotherapy.
[0031] The present invention also provides a method of inhibiting
the formation of metastases in a warm-blooded animal having a
breast tumor disease which comprises administering to the patient a
pharmaceutically effective amount of a COMBINATION OF THE INVENTION
in a quantity which is jointly therapeutically effective against
said tumor disease and in which the compounds can also be present
in the form of their pharmaceutically acceptable salts.
[0032] In one embodiment of the invention, a compound of formula I
is administered to a human subject less frequently than on a daily
basis. In particular, such embodiment relates to a treatment
regimen whereby over at least a three week period, a compound of
formula I is administered on only about 40% to about 71% of the
days. In such embodiment, specifically, the present invention
relates to a method of treating a human subject with a compound of
formula I, which comprises administering such pyrimidine derivative
to the human subject from three to five times in each seven day
period for a period of three weeks or longer, more specifically,
three or four times a week on alternate days for a period of three
weeks or longer. In a more specific embodiment, a compound of
formula I is administered three times each week on alternate days,
for example, on Monday, Wednesday and Friday of each week, for at
least three weeks. Preferably, such dosage regimen is carried out
through at least four or more weeks, for example 4, 5, 6, 7 or 8
weeks.
[0033] Alternatively, a compound of formula I is administered daily
in cycles comprising a period of one to four weeks, e.g. two weeks,
which is optionally followed by a period of one to three weeks,
e.g. two weeks, without administering the compound to the patient.
The whole treatment period consisting of such cycles can amount,
e.g., to about 6, 12 or 18 months. Furthermore, the present
invention pertains to the use of a COMBINATION OF THE INVENTION for
the treatment of a solid tumor disease and for the preparation of a
medicament for the treatment of a solid tumor disease.
[0034] Furthermore, the present invention pertains to the use of a
COMBINATION OF THE INVENTION for the treatment of a solid tumor
disease and for the preparation of a medicament for the treatment
of a solid tumor disease.
[0035] Additionally, the present invention pertains to the use of
letrozole in combination with a 7H-pyrrolo[2,3-d]pyrimidine
derivative of formula I wherein q is 1, R.sub.2 is phenyl
substituted by hydroxy, and R.sub.6 is hydrogen or methyl, for the
preparation of a medicament for the treatment of a solid tumor
disease.
[0036] Moreover, the present invention provides a commercial
package comprising as active ingredients COMBINATION OF THE
INVENTION, together with instructions for simultaneous, separate or
sequential use thereof in the treatment of a solid tumor
disease.
* * * * *